Rodents, and liver cells in culture, will be exposed to the hepatotoxins CCl4, dimethylnitrosamine, ethionine and thioacetamide, comparing both necrogenic and non-necrogenic injury and agents activated by the mixed function oxidase system and those active through alternative pathways. Specific attention will be directed toward the early phase of injury (first 6 hours) and a late phase (48-120 hours) in which specific phenotypic expression occurs. An analysis of toxin metabolism and the interaction of this metabolism with the endoplasmic reticulum will be followed in vivo and in vitro. An attempt will be made to separate adduction and peroxidation as mechanisms in CCl4 poisoning, specifically with regard to cytochrome P450 destruction. A search for a diffusible product of a metabolic cascade, potentially responsible for altering protein synthesis will be sought. The mechanism of disruption of and of selection for specific protein synthesis will be sought. An analysis of plasmalemma function will be tested using both cell suspensions and isolated function. Specific search for alterations in metal ion activated ATPase and calcium flux changes will be sought. Critical structural and functional analysis will be included. These studies will provide an understanding of the physiological alterations in cell injury and cell death.